This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The principal goal of this project is to obtain pilot data for a grant proposal aimed at exploring effective treatments for individuals suffering from PTSD. Post-traumatic stress disorder (PTSD) is a chronic and common anxiety disorder that follows exposure to an overwhelming traumatic event. The majority of patients with PTSD also meet criteria for other psychiatric disorders and many attempt suicide. Despite its substantial costs to society, little is known about the etiology or pathophysiology of this disorder. While PTSD is somewhat responsive to pharmacological treatments such as selective serotonin reuptake inhibitors (SSRIs), response rates rarely exceed 60%, and even fewer patients (20-30%) achieve clinical remission. Once psychopathology emerges, PTSD is often associated with pervasive and debilitating symptoms that persist despite aggressive treatment interventions. Thus, there is a clear need to develop novel and improved therapeutics for PTSD. We propose to study a pharmacological intervention that aims to decrease the intrusive unwanted memories of the trauma, which are often the most severe and troubling component of PTSD symptoms. We propose to do this by using mifepristone to interrupt reconsolidation of the unwanted memories. Our intervention is based on the fear-conditioning model of PTSD that considers intrusive, involuntary, repetitive, and vivid emotionally-laden memories of a trauma as pivotal to the development of PTSD. Such memories are a typical component of the initial response to traumatic events in both healthy individuals and patients with PTSD. For healthy individuals, however, the intrusive quality and emotional charge of these memories tends to gradually diminish over time, whereas individuals with PTSD do not exhibit any attenuation in symptoms. One potential reason for the persistence of traumatic memories may be that in vulnerable individuals, memories of traumatic events are more indelibly encoded, consolidated, and perpetually reconsolidated, which is thought to inhibit the normal process of extinction observed in healthy individuals. Hypothesis: We hypothesize that mifepristone may represent a pharmacological treatment that, used in tandem with memory reactivation with imaginal exposure, may alleviate symptoms of PTSD. We also hypothesize that the stress modulatory pathway is an easily accessible and fundamental target for the development of new treatments for PTSD. Therefore, in this grant, we propose to conduct a clinical trials of PTSD patients using imaginal exposure in tandem with mifepristone administration. Specific hypotheses: Our primary objective is to determine if mifepristone is an effective treatment for the intrusive unwanted memories associated with PTSD when used in the context of reactivating a traumatic memory to interrupt reconsolidation of that memory. We believe that we are in a unique position to investigate novel therapeutic approaches based on memory reconsolidation disruption for the treatment of PTSD. The results from animal studies underway at Mount Sinai (In Dr. Cristina Alberini's lab) played a critical role in designing our clinical trial. Clinical Trial: Hypothesis 1: Mifepristone disrupts the reconsolidation of traumatic memories in an animal model, therefore, we will test whether mifepristone, which is a well tolerated in humans and have been extensively used in clinical settings as an abortofacient, and has been studied extensively in the treatment of psychotic depression, is effective in treating PTSD. We specifically predict that patients treated with two doses of mifepristone will show a greater decrease in subjective distress and less physiological arousal as measured by heart rate (HR), blood pressure (BP) and skin conductance (SC) while the listening to the trauma scripts one week later.